Ataxia-telangiectasia (AT) is a recessively inherited disease of humans characterized by radiation hypersensitivity and a greatly increased incidence of cancer, as well as a diverse collection of other significant clinical features. AT patients have a greater than 60 fold increased incidence of cancer compared to age matched controls, and both the patients and their cultured cells are extremely sensitive to gamma irradiation. Therefore, a knowledge of the underlying defect in AT would contribute substantially both to our understanding of the mechanisms of human responses to ionizing radiation, and the basis of genetic cancer susceptibility. Although AT within a given family is inherited as a single recessive trait, four AT complementation groups have been defined based on the phenotype of radioresistant DNA synthesis (RDS). Our prior genetic studies of AT families localizes the genes for the 2 largest complementation groups (encompassing approximately 85% of all cases) to a region of 8.1 centimorgans on human chromosome 11. In this application, we propose to isolate these genes by physical mapping and isolation DNA sequences from this region on YAC clones. We will screen these cloned DNA sequences for the presence of AT genes by a variety of techniques. Ultimately, identification of an AT gene will be confirmed by correction of the radiosensitivity and radiation resistant DNA synthesis phenotypes of cultured AT fibroblasts. Isolation of a gene for AT will allow us to investigate the role of different mutant alleles in cancer susceptibility and in radiation sensitivity by retrospective genetic association studies in existing patient populations, and the development of a murine AT model for prospective testing of models of carcinogenesis and radiation sensitivity.